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Pediatric Pharmacotherapy
A Monthly Review for Health Care Professionals of the Children's
Medical Center
Volume 4 Number 8, August 1998
Mycophenolate mofetil: Use in pediatrics
Beth Ann Fullmer, R.Ph., Pharm.D. Candidate
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Introduction
Mechanism of Action
Current Indications
Use in Children
Pharmacokinetics
Drug Interactions
Adverse Reactions
Dosing and Monitoring
Conclusion
References
Pharmacology Literature Reviews
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Tacrolimus absorption during enteral feedings
In 1946, Sir Howard Florey first demonstrated the ability of mycophenolic acid
(MPA) to inhibit bacteria, fungi, and leukocytes.1 Investigated for its
antineoplastic activity in the 1970’s, MPA has since demonstrated additional
benefit in treating psoriasis and has been further studied for its antimicrobial
properties.2-5 In the late 1980’s, studies in animals demonstrated the
immunosupressive characteristics of MPA. This work led to the formulation of a
prodrug, mycophenolate mofetil (MMF), and human trials which established its
efficacy in preventing acute rejection in renal, liver, and heart transplants.6 Since
that time, numerous protocols have been devised which substitute MMF for
azathioprine, using it in combination with cyclosporine and corticosteroids.
Mechanism of Action
MPA, the active form of MMF, inhibits immunologically mediated inflammation,
preventing organ rejection. The primary site for MPA activity is the de novo
pathway responsible for adenosine and guanosine biosynthesis in human cells.
MPA blocks the rate-limiting enzyme inosine monophosphate dehydrogenase
(IMPDH) in this pathway, depleting guanosine and causing a relative increase in
adenosine, both of which ultimately inhibit the proliferation of de novo
dependent T- and B-lymphocytes.7 Other cell lines, capable of purine
biosynthesis by shifting to the salvage pathway, are left relatively unaffected.
Additionally, MPA impedes B-lymphocyte antibody production and, through
suppressing glycoproteins responsible for cellular adhesion, inhibits leukocyte
recruitment to inflammation and graft rejection sites.8,9
Current Indication
MMF is approved for the prevention of renal and cardiac allograft rejection when
combined with cyclosporine and steroids in adults.9
Use in Children
Several reports of MMF use in pediatric patients have been published over the
decade. These papers consist of a mix of retrospective reviews, clinical trials,
case series, and case reports.10-19
There have been several papers targeting children under the age of 12 years. In
1997, Boucek and colleagues10 reported success with a combination strategy of
MMF and antithymocyte serum (ATS) in 18 consecutive children undergoing
orthotopic heart transplantation. The authors compared this sample to the
preceding 22 transplanted children who served as historical controls. Routine
perioperative cyclosporine (CyA), azathioprine (AZA), and steroids were
administered, followed by a protocol of ATS for 3 days and 6 weeks of 30-50
mg/kg/day MMF combined with CyA. For CMV-positive recipients or donors,
ganciclovir was used during ATS and was followed by acyclovir during MMF.
Seventeen patients completed the protocol. The number of rejection episodes
per 100 days for the MMF patients was 0.23 versus 0.45 for the AZA and CyA
controls. Infection rates were comparable. Gamma glutamyltransferase and
absolute neutrophil counts were comparable to the controls. Mortality for the
control group was 23% versus 5.5% for the MMF-treated group.10
Also last year, Ettenger and coworkers11 published a 2 year retrospective review
of MMF as maintenance immunosuppression in pediatric renal transplantation.
Thirty-seven patients from 2 to 20 years of age received MMF with CyA and
prednisone. The average length of therapy was 11 months, and the MMF dosage
ranged from 16-60 mg/kg/day, in 2 divided doses. Reported toxicities included
neutropenia (8%), diarrhea, and nausea (16% each). Cytomegalovirus (CMV)
infection was observed in 19% of the patients, bacterial infection in 8%, and 5%
had oral thrush or herpes stomatitis.
Nine of 12 available biopsy results from these children were normal or showed
only borderline acute rejection changes. One patient had mild acute rejection
and 2 patients had mild interstitial mononuclear cellular infiltrates with otherwise
insignificant clinical findings. Two of the 12 had moderate chronic nephropathy.
Glomerular filtration rate studies and calculated creatinine clearance revealed no
significant reduction or improvement in renal function. Mean daily prednisone
doses were 0.098 mg/kg in the MMF group, compared to 0.17 mg/kg for the
matched controls. The authors concluded that MMF was a useful addition to
immunosuppressive therapy and are currently using a MMF dose of 600
mg/M2/day.11
The use of MMF for intestinal transplantation was also reported in 1997. Of the
19 patients studied by Tzakis and colleages12, 5 were children. MMF was started
at a dosage of 30 mg/kg/day in two divided doses in 3 of the children initially
after transplant. Two others were switched to MMF after being treated for
rejection which occurred during CyA immunosuppression.
Additional reports of MMF use as rescue therapy after rejection have also been
published. MMF doses of 18-50 mg/kg/day, given in two divided doses for 6
months, were described in a study of 37 liver transplantation patients. Four of
the patients enrolled in this rescue protocol were under the age of 12.13
A case report published in Lancet in 1996 described a 2 year old renal transplant
patient who received MMF after developing anuria and biopsy-proven acute
rejection on her initial immunosupressive regimen of antithymocyte globulin, CyA
and acyclovir. Eight days after initiating MMF, her renal function began to
improve, eventually returning to baseline values. A subsequent episode of
rejection was managed with muromonab-CD3 while she remained on MMF
maintenance therapy. At last evaluation, 11 months post-transplant, the child
was rejection-free on MMF 375 mg/day and CyA.14
In addition to these studies involving young children, several other studies have
included preadolescent and adolescent patients. The children in these reports
have been treated with MMF dosage regimens of 1000 mg to 1500 mg per day
after kidney, lung, or liver transplantation.15-19
Pharmacokinetics
MMF is well absorbed after oral administration and rapidly hydrolyzed in the liver
to MPA, the active drug. The time to maximum plasma concentration is
approximately 2 hours following oral administration, with a secondary peak
occurring within 6 to 12 hours. This secondary peak results from enterohepatic
recycling of an inactive metabolite, mycophenolic acid glucuronide (MPAG). The
volume of distribution of MPA in adults is approximately 4 L/kg. MPA is 97%
bound to serum albumin. MPAG is also highly protein bound and may compete
with MPA for binding sites, resulting in greater free drug.9,20
The conversion of MPA to MPAG takes place primarily in the liver, but may also
occur via b-gluronidases in other cells.7,9 Hepatic insufficiency due to alcoholic
cirrhosis does not appear to alter the metabolism of MPA; however, other
etiologies for hepatic disease may produce a different metabolic profile.
MPAG is eliminated by renal excretion. Less than 1% of an oral dose is
eliminated as unchanged MPA. MPAG accumulates in patients with severe chronic
renal impairment. Neither MPAG nor MPA are significantly removed by
hemodialysis.
Drug Interactions
Pharmacokinetic
Decreased MPA concentrations have been observed with concomitant
administration of MMF and antacids or cholestyramine, likely the result of
interference with enterohepatic recirculation. Antibiotics which alter
gastrointestinal flora may also impair this pathway. Competition for protein
binding sites may elevate serum concentrations of theophylline or phenytoin
when given with MMF, increasing free drug by 10%.
Since MPAG is eliminated by renal tubular secretion, administration with
acyclovir, ganciclovir, or probenecid which compete for or alter renal tubular
secretion, may increase serum concentrations of both drugs. This drug
interaction is likely to be most pronounced in patients with high MPAG
concentrations resulting from severe renal impairment or delayed graft function.
Pharmacodynamic
Immunosuppressive agents used in conjunction with MMF to prevent or treat
allograft rejection may result in additive risk for severe bone marrow
suppression.9
Adverse Reactions
The principal adverse reactions associated with MMF are vomiting, diarrhea,
leukopenia, and an increased incidence of infection. Additionally, gastrointestinal
hemorrhage has been observed in 2-3% of transplanted patients receiving MMF.
Post-marketing experience has also revealed reports of colitis and pancreatitis.
Care should be taken when administering MMF to patients with active digestive
system disease.9
Data collected from 3 double-blind controlled trials for the prevention of renal
transplant rejection and 1 double blind comparative trial for the prevention of
cardiac transplant rejection have generated the following observations:
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Severe neutropenia occurred in up to 2% of the renal patients and 2.8% of the
cardiac patients.
In the cardiac population, opportunistic infections were approximately 10%
higher in MMF-treated patients compared to those treated with AZA, but did not
lead to an increase in mortality due to infection/sepsis.
Patients with renal transplants who were treated with MMF had a higher
incidence of sepsis, primarily CMV, than patients receiving AZA or placebo;
cardiac patients showed no difference.
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Similar rates of fatal infection/sepsis (<2%) occurred in patients receiving either
MMF or AZA after cardiac or renal transplantation.
The incidence of malignancies for patients with renal transplants was similar in
patients treated with MMF to previously reported data with other
immunosuppressive regimens.
Lymphoproliferative disease or lymphoma occurred in 1% of the population
receiving MMF during clinical trials. This was a slight increase over previous
data with AZA in renal patients. Non-melanoma skin carcinoma occurred in 1.64.2% of transplant patients treated with MMF, compared to 2.4% previously
reported with AZA. Other malignancies were observed in 0.8-2.1% of MMF
patients (both renal and cardiac), similar to values reported for AZA or
placebo.9,20
Dosing and Monitoring in Pediatric Patients
The studies and cases previously described have established an initial MMF
dosage range of 16 to 60 mg/kg/day, usually divided into two doses, for patients
from 0.5 to 20 years of age.10-13 The initial dose of MMF should be given as soon
as possible following transplantation. Patients with severe renal impairment
during the immediate post-operative period should be followed closely because
of potential drug accumulation and bone marrow suppression.
Complete blood counts should be monitored at least weekly during the first
month of MMF therapy, then twice monthly for 2 months, and then monthly for
the remainder of the first post-transplant year. If the absolute neutrophil count
falls to less than 1.3 x 103/µ L, further diagnostic tests should be performed to
evaluate the need for reduction or interruption of MMF therapy.
MMF is available as 250 mg capsules and 500 mg tablets (CellCept ; Roche
Laboratories). Methods for preparing an extemporaneous oral liquid have been
recently published, allowing more precise dosing adjustments in younger
children. The 100 mg/ml suspension retains more than 90% potency for 4
months, whether refrigerated or stored at room temperature. Since MMF is a
possible teratogen (pregnancy category C20), care should be taken when
compounding or administering the suspension to avoid exposure of health care
professionals and family members to the capsule powder or the resulting liquid.21
An injectable formulation of MMF was approved by the Food and Drug
Administration earlier this month. The injection will also be sold under the brand
name CellCept by Roche.22
Conclusion
MMF appears to be an effective addition to the immunosuppressive
armamentarium. Further studies need to be done to define the role of MMF in
pediatric transplant patients. Areas for research include the long-term impact of
MMF on graft survival in children, potential for steroid dose reduction, and
reversal of resistant rejection episodes.
References
1. Florey HW, Gilliver K, Jennings MA, et al. Mycophenolic acid: An antibiotic
from Penicillium breicompactum. Lancet 1946;1:46-9.
2. Williams RH, Lively DH, Delong DC, et al. Mycophenolic acid: Antiviral and
antitumor properties. J Antibiot 1968;21:463-4
3. Carter SB, Franklin RJ, Jones DF, et al. Mycophenolic acid: An anticancer
compound with unusual properties. Nature 1969;223:848-50.
4. Suzuki S, Kimura R, Ando K, et al. Antitumor activity of mycophenolic acid. J
Antibiot 1969;22:297-302.
5. Jones EL, Epinette WW, Hackney VC, et al. Treatment of psoriasis with oral
mycophenolic acid. J Invest Dermatol 1975;65:537-42.
6. Lee W, Gu L, Miksztal AR, et al. Bioavailability improvement of mycophenolic
acid through amino ester derivatization. Pharm Res 1990;7:161-6.
7. Allison AC, Eugui EM. The design and development of an immunosuppressive
drug, mycophenolate mofetil. Sem Immunopath 1993;14:358-80.
8. Allison AC, Eugui EM. Preferential suppression of lymphocyte proliferation by
mycophenolic acid and predicted long-term effects of mycophenolate mofetil in
transplantation. Transplant Proc 1994;26:3205-10.
9. Product information. CellCept. Roche Laboratories, Nutley, New Jersey. February
1998.
10. Boucek MM, Pietra B, Sondheimer H, et al. Anti-T-cell-antibody prophylaxis in
children: Success with a novel combination strategy of mycophenolate mofetil
and antithymocyte serum. Transplant Proc 1997;29(8A):16S-20S.
11. Ettenger R, Cohen A, Nast C, et al. Mycophenolate mofetil as maintenance
immunosuppression of pediatric renal transplantation. Transplant Proc
1997;29:340-1.
12. Tzakis AG, Nery JR, Thompson J, et al. New immunosuppressive regimens in
clinical intestinal transplantation. Transplant Proc 1997;29:683-5.
13. Gavlik A, Goldberg MG, Tsaroucha A, et al. Mycophenolate mofetil rescue
therapy in liver transplant recipients. Transplant Proc 1997;29:549-52.
14. Songok EM, Libondo DK, Rotich MC, et al. Mycophenolate mofetil to rescue
children with acute renal transplant rejection. Lancet 1996;347:1699-700. Letter.
15. Sollinger HW, Belzer FO, Deierhoi MH, et al. RS-61443 (mycophenolate
mofetil): A multicenter study for refractory kidney transplant rejection. Ann Surg
1992;216:513-9.
16. Zuckerman A, Birsan T, et al. Mycophenolate mofetil in lung transplantation.
Transplant Proc 1998;30:1514-6.
17. The Mycophenolate Mofetil Renal Refractory Rejection Study Group.
Mycophenolate mofetil for the treatment of refractory, acute, cellular renal
transplant rejection. Transplantation 1996;61:722-9.
18. Ringe B, Braun F, Lorf T, et al. Tacrolimus and mycophenolate mofetil in clinical
liver transplantation: Experience with a steroid-sparing concept. Transplant Proc
1998;30:1415-6.
19. Filler G, Ehrich J. Mycophenolate mofetil for rescue therapy in acute renal
transplant rejection in children should always be monitored by measurement of
trough concentrations. Nephrol Dialysis Transplant 1997;12:374-5.
20. Mycophenolate mofetil. In: Olin BR ed. Drug Facts and Comparisons. St. Louis:
Facts and Comparisons, Inc. 1998:737l-738.
21. Anaizi NH, Swenson CE, Dentiger PJ. Stability of mycophenolate mofetil in an
extemporaneously compounded oral liquid. Am J Health-Syst Pharm
1998;55:926-9.
22. Roche CellCept. F-D-C Reports, "The Pink Sheet" 1998;60(33):31.
Pharmacology Literature Review
Tacrolimus Absorption During Enteral Feeds
While this study was conducted in adult organ transplant recipients, the results
have application within the pediatric population as well. Ten liver or lung
transplant patients receiving tacrolimus (FK 506) were given nasoduodenal feeds
with Osmolite on two consecutive days. On one day, tacrolimus was
administered during feedings; and on the other, the feeding was held from 1
hour prior to 8 hours after each dose. Serial serum samples were obtained to
document drug absorption and the results were compared with a paired t-test.
The authors found no significant difference in time to reach peak serum
concentrations, dose-adjusted trough concentrations, maximum blood
concentrations, or area under the concentration curves between the two feeding
methods. As a result, they concluded that concurrent enteral feeding does not
affect oral tacrolimus absorption. Murray M, Grogan TA, Lever J, et al.
Comparison of tacrolimus absorption in transplant patients receiving continuous
versus interrupted enteral nutritional feeding. Ann Pharmacother
1998;32:633-6.
Contributing Editor: Marcia L. Buck,
PharmD
Editorial Board: Anne E. Hendrick, PharmD
Michelle W. McCarthy, PharmD
Production manager: Stephen M. Borowitz
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All contents copyright (C) 1995, Stephen M. Borowitz, M.D., Children's Medical
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1998